The long term goal of this proposal is to develop a molecular understanding, derived from first principles, of the stages that bridge between the deposition of high energy in the environment of DNA and the development of permanently damaged DNA. The plan presented below focuses on the chemistry of the indirect damage, defined as the interaction between DNA and the reactive species produced in its environment. The working hypothesis of the proposal is that indirect damage is controlled by rate constants of the reactions between the reactive species and DNA. These rate constants depend on the collision between the reactive species and DNA, on the rates of subsequent chemical reactions, and on the rates of scavenging of these radicals. Also, the dynamic structure of DNA has an important influence on the overall yield and rates of indirect damage. We will use a combination of theoretical methods which are especially designed to address the specific problems in each of the sections of the proposal. The first deals with the characterization of the collision event between reactive particles and components of DNA (e.g., bases, sugars, and nucleotides) as well as models of single and double stranded DNA. Using Brownian dynamics simulations we plan to compute the rate constants and statistical distribution of diffusion controlled collisions determined by long range forces between DNA and the reactive particles. The second section deals with those bimolecular reactions that are governed by breakage and formation of chemical bonds (e.g., OH addition to bases and H- abstraction from sugar by OH). The rate constants for these reactions are composed from the diffusion controlled collisions and from the efficiency of the chemical event determined by the barriers. The energetic barriers for these reactions will be calculated with quantum chemical methods. In the third section we propose to construct an integrated representation of the interaction of the reactive species with dynamically fluctuating DNA. Results from Brownian dynamics simulations and quantum chemical studies will be supplemented by Molecular dynamics simulations to provide an integrated description of collisions and interactions between reactive particles and dynamically active DNA. These studies, in addition to providing rates and probabilities of distribution of initial damage in DNA, will become the theoretical basis for the evaluation f the importance of oxygen in damage "fixing" and of scavengers in providing protection against indirect damage to DNA.